There are many disorders known wherein the proliferation of fibrotic tissue is a characteristic feature. Examples of such disorders include, for example, rheumatoid arthritis, chronic arthritis, osteoarthritis, hepatic fibrosis, hepatic cirrhosis, pulmonary fibrosis, renal fibrosis, cardiac fibrosis, arteriosclerosis tumour-associated fibrosis and the formation of scar tissue following injury or surgery. Thus, a therapeutic agent which possesses anti-fibrotic properties may be of value in the treatment of one or more of these disorders.
It is known that the enzyme prolyl 4-hydroxylase is involved in the hydroxylation of proline residues in collagenous protein, and that 4-hydroxyproline residues are essential for the formation of the characteristic triple helical form of collagen which is secreted into fibrotic tissue. Consequently, a compound which inhibits the activity of prolyl 4-hydroxylase may be of potential value in the treatment of fibroproliferative disease, which is characterized by excessive collagen production.
Various chemical compounds have been reported to inhibit prolyl 4-hydroxylase; for example, 2,2'-dipyridyl (W. Muller et al., FEBS Letters, 90:218 (1978)), pyridine-2,4-dicarboxylic acid (K. Majamaa et al., Eur.J.Biochem., 138:239 (1984)), pyridine-2,4-dicarboxlic acid derivatives and pyridine-2,5-dicarboxylic acid deivatives (European Patent Application Nos. 278452, 278453, 278454 and 281943) and heterocyclic carbonylglycines (T. J. Franklin et al., Biochem. Soc. Trans., 19:812-815 (1991)).
Despite previous efforts, a need exists for safe and effective means for the treatment of fibroproliferative diseases and disorders.